In recent years, fluorinated ethers have been discovered which have useful anesthetic properties via inhalation. Included among these anesthetics are desflurane (CF.sub.3 CHFOCHF.sub.2), isoflurane (CF.sub.3 CHClOCHF.sub.2), enflurane (HClFCCF.sub.2 OCHF.sub.2), and sevoflurane ((CF.sub.3).sub.2 CHOCH.sub.2 F). Sevoflurane is an advantageous inhalation anesthetic because of its rapid onset of anesthesia and rapid recovery, which are desirable characteristics of modern day inhalation anesthetics. Sevoflurane is administered by the inhalation route to warm-blooded, air-breathing animals in an amount of from about 1% to 5% by volume in admixture with oxygen or a gaseous mixture containing oxygen in an amount sufficient to support respiration.
U.S. Pat. Nos. 3,683,092 and 3,689,571 disclose the use of sevoflurane as an inhalation anesthetic and its synthesis by reaction of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with excess potassium fluoride in a high boiling solvent, sulfolane, at 120.degree. C. to replace the chlorine of the chloromethyl group with fluorine. These patents also disclose a method of producing sevoflurane by reaction of hexafluoroisopropanol with dimethyl sulfate and sodium hydroxide solution, and subsequent fluorination of the resulting methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with bromine trifluoride. U.S. Pat. No. 4,328,376 discloses separation of sevoflurane from a by-product olefin produced in a process similar to that described in U.S. Pat. No. 3,689,571.
Other synthetic routes to sevoflurane are found in the following patent publications: U.S. Pat. No. 3,897,502--fluorination of methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with 20% fluorine in argon; U.S. Pat. Nos. 4,250,334 and 4,469,898--fluoromethylation of hexafluoroisopropanol utilizing hydrogen fluoride, formaldehyde and sulfuric acid or other dehydrating agents; U.S. Pat. No. 4,874,901--reaction of chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with neat potassium fluoride under conditions of high temperature and pressure; and PTC Int. Appl. WO 97 25,303--reaction of hexafluoroisopropanol with bis(fluoromethyl)ether.
Okazaki, et. al. in J. Fluorine Chem. 1974, 4(4), 387 describe an electrochemical fluorination that gives a fluoromethyl ether. German Patent No. 25 20 962 describes a synthesis of fluoromethyl ethers from chloromethyl ethers with hydrogen fluoride at 125.degree.-149.degree. C. in the presence of chromium oxyfluoride. Bensoam, et. al. in Tetrahedron Lett. 1979, 4, 353 describe a synthesis of fluoromethyl ethers by halogen exchange with tetraalkylfluorophosphoranes. Finally, German Patent No. 28 23 969 discloses a process for preparing organofluorine compounds, including monofluoromethyl ethers, by reaction of corresponding organochlorides or bromides with selected amine hydrofluorides. Triethylamine hydrofluoride and piperidine hydrofluoride are specific examples of fluorinating agents used for the preparation of such organofluorine compounds, which are typically produced in yields of from about 40 to 80%.
In accordance with the present invention, a synthesis of certain monofluoromethyl ethers, in particular sevoflurane, is provided which is characterized by improved yields over previously known methods.